Balanced Fluid Resuscitation to Decrease Kidney Injury in Children with Septic Shock
Study ID: STU-2020-0661
What is PRoMPT BOLUS?
PROMPT BOLUS (PRagMatic Pediatric Trial of Balanced vs nOrmaL Saline FlUid in Sepsis) is a clinical trial to compare two commonly used treatments for pediatric sepsis to see if one is more effective and safer than the other. The treatments in this study are two different intravenous (IV) fluid types. One fluid type is 0.9% “normal” saline (NS) and the other is balanced fluids (including lactated Ringer’s [LR] or Plasma-Lyte [PL]).
What is sepsis?
Sepsis is a potentially life threatening response to infection that
- Affects over 70,000 children in the United States every year
- Can happen to someone of any age
- Can cause damage to many of the body’s organs
- Can prevent a person from being able to function normally or independently
- Can limit awareness and cause coma
- Can cause death
How is sepsis treated?
Sepsis is treated with emergency therapies that include antibiotics and fluids, usually given through an IV. The most common place for sepsis to be treated when it occurs in the community is in an emergency department (ED).
What is PRoMPT BOLUS?
PRoMPT BOLUS is a clinical trial to compare two IV fluid treatments for pediatric sepsis. One fluid type is 0.9% normal saline (NS) and the other is balanced fluids (including lactated Ringer’s [LR] or Plasma-Lyte [PL]). Both fluid types are commonly used and both are helpful to treat pediatric sepsis but we do not yet know which fluid type is the safest and most effective.
PRoMPT BOLUS began as pilot version at CHOP that helped us to improve the design of the study in the best possible way. The next phase is a multicenter clinical trial involving over 20 US sites through the Pediatric Emergency Care Applied Research Network (PECARN), as well as study sites in Canada, Australia, and New Zealand. Across all sites, PRoMPT BOLUS will ultimately enroll over 8,000 children with sepsis.
PRoMPT BOLUS will enroll children over 6 months and less than 18 years of age with possible sepsis during a CHOP emergency department visit. Children will be considered to have possible sepsis if their doctor thinks they may have sepsis that will require treatment with both IV antibiotics and IV fluids and their doctor is worried about possible shock. The study will include children who are previously healthy, as well as children with chronic medical problems.
Frequently Asked Questions
How will the study work?
If a child is enrolled in PRoMPT BOLUS, they will be randomly assigned during their ED visit (like the flip of a coin) to receive either NS or balanced IV fluids as part of their sepsis treatment. Most patients who are randomized to balanced fluids will be treated with lactated Ringer’s (LR), but other balanced fluids, such as Plasma-Lyte, may be substituted as per institutional or doctor’s preference. They will then receive study fluid as their treatment fluid during the remained of their ED visit and for up to 48 hours of their hospitalization if they are admitted to the hospital. The child’s doctors will determine when to give fluid and how much fluid to give, just as they would for a child not in the study.
What is the difference between NS and LR?
Both NS and balanced fluids are electrolyte solutions- forms of salt water- that are safe, FDA-approved, and commonly used to treat sepsis. At CHOP, about half of children admitted to the Pediatric Intensive Care Unit (PICU) are treated with NS and half are treated with balanced fluids (LR at CHOP). The chemical composition of NS and balanced fluids are slightly different in that NS has only sodium and chloride, while balanced fluids contain less sodium, less chloride, and also has small amounts of other electrolytes like magnesium and potassium.
Why is this study being done?
Although both NS and balanced fluids are safe, FDA-approved, and commonly used to treat sepsis, nobody knows for sure whether one fluid is more effective and safer to treat sepsis than the other. Several prior studies have suggested that balanced fluids may be superior to NS, but a clear determination cannot be made without a large clinical trial. In pediatrics, NS is generally the preferred fluid used to treat sepsis but balanced fluids (particularly LR) are also commonly used, especially for children admitted to the CHOP Pediatric Intensive Care Unit (PICU). However, nobody yet knows for sure which fluid is safer or more effective.
What are the risks of study participation?
Because both fluid types are effective, safe and recommended for treatment of sepsis, all children in this study will receive standard care, regardless of which fluid is given. But because, as part of this study, you will be randomly assigned (like a "flip of a coin") to receive either NS or balanced fluids rather than your doctor selecting which fluid to give you, you may receive a fluid that you might nor have otherwise received. If there are differences in effectiveness and safety between these two fluids, then length of stay in hospital or other outcomes may be different depending on the fluid you receive and one fluid may have higher mortality than other.
Taking blood may cause some pain, bleeding or bruising at the spot where the needle enters your body. Rarely, taking blood may cause fainting or infection. Whenever possible, blood collection will be done at the same time as clinical tests.
Will the study affect any other part of a child’s treatment for sepsis?
NO. Decisions about when and how much fluid a child receives, as well as any other medications that they might need will not be affected by the study. These will be decided by the treatment team as they normally would for any child with possible sepsis.
What if my child is enrolled in the study and I change my mind about wanting them to participate?
A subject is free to withdraw from study participation at any time by contacting the study team either in person or by email: PRoMPTBOLUS@email.chop.edu
What if I have questions or concerns about EFIC?
We encourage you to contact us with any questions/concerns and/or complete an online survey, so that we may work together to share information about patient enrollment through EFIC and learn from each other.
What if I do not want my child to participate in the study at all?
If you would like to opt your child out of the study so that they would not be included if they developed possible sepsis, please fill out this form. Any patient who has opted out will be mailed a bracelet that they must wear for the duration of the study so that they will not be enrolled even if they present to the CHOP or another study site emergency department with possible sepsis.
1. For general study inquiries or for study-related questions, please complete the form below.
2. To complete an on-line REDCap survey, click here.
3. To “opt-out” of the PRoMPT BOLUS clinical trial, click here.
How is PRoMPT BOLUS different from other clinical trials?
Most clinical trials outline very strict eligibility criteria for enrollment and provide an extensive protocol of therapy for subjects in the study. However, PRoMPT BOLUS is a pragmatic clinical trial, which means that the study conditions mimic “real life” as much as possible with simple inclusion criteria, few exclusion criteria, and very few elements of care that are protocolized. Our goal is to compare NS and balanced fluids as they may be used in ordinary clinical care.
Exception from Informed Consent (EFIC)
Ethical standards required that researchers get permission before a person can be included in a study through a process termed prospective informed consent. When time permits and it is safe to do so, we will ask permission before a person is enrolled into PRoMPT BOLUS. However, we realize that most people suffering from sepsis will be too sick to give consent and, since sepsis must be treated quickly, there may not be enough time to locate and talk to the person’s parent, guardian, or legal representative about the study. We anticipate that most patients will need be enrolled in the study without his/her legal representative’s consent. This is called “Exception from Informed Consent” (EFIC). Once the representative is located or the patient improves, they will be told about the study and asked for permission to continue in the study
Exception from Informed Consent (EFIC)
What is Exception From Informed Consent (EFIC)?
The U.S. Food and Drug Administration (FDA) is an agency of the federal government that oversees human research protection involving medicines. The FDA has created a set of special rules, called “Exception From Informed Consent” (EFIC), for clinical trials that apply to critically ill patients who require emergent therapy when prospective informed consent is not possible or may put the patient at risk for increased harm by delaying potentially life-saving therapies. Under some circumstances, there may not be time to seek prospective informed consent from every eligible patient and, in some cases, discussing a possible option to enroll in a study may itself cause dangerous delays in a person’s care. Nonetheless, many critically ill patients could benefit from enrollment into an appropriate clinical trial. Therefore, to ensure that clinical trials can be conducted for patients in emergency situations, the FDA established rules for EFIC that require special safeguards to ensure that most people would consider the study to be ethical and appropriate. These special rules allow research studies in certain emergency situations to be conducted without prospective informed consent.
EFIC can only be used when:
- The person’s life is at risk, AND,
- The best treatment is not known, AND
- The study might help the person, AND
- It is not possible to get permission:
- from the person because of his or her medical condition nor
- from the person’s guardian because there is a very short amount of time required to treat the medical problem
Before researchers can start a study using EFIC, they must provide information about the study to the community and get their feedback. We have conducted surveys and performed focus groups with CHOP families for our pilot study, and will extend this work to Pittsburgh for this phase of the study.
For Medical Providers
Approximately 2,500 non-newborn children die from septic shock each year in the US and thousands more die worldwide. Despite widespread implementation of resuscitation protocols, contemporary studies still report 2-6% mortality for children with septic shock treated in the pediatric ED.
Crystalloids are the standard resuscitative fluid for septic shock. NS and balanced fluids are inexpensive, stable at room temperature, and nearly universally available with identical storage volumes and dosing strategies. Notably, both are also of proven clinical benefit in septic shock. However, NS is used in 80-95% of cases of pediatric septic shock, despite data supporting that LR or other balanced fluid resuscitation may have superior efficacy and safety.
NS contains a supra-physiologic concentration of chloride (1.5X that of plasma) and a strong ion difference (SID) of zero but is isotonic compared to extracellular fluid. Balanced solutions have less chloride, small amounts of additional electrolytes, and a higher SID due to the presence of an anion buffer. The high chloride content and low SID of NS has been associated with acute kidney injury (AKI), acidemia, hyperkalemia, vascular permeability, inflammation, coagulopathy, fluid overload, and death
Buffered crystalloids, have demonstrated a 1-4% absolute mortality reduction and up to a 50% lower odds of dialysis compared to NS in observational and non-randomized interventional studies in adult sepsis. Nevertheless, because definitive conclusions have not been able to be drawn from existing observational and non-randomized studies, NS overwhelmingly remains the most commonly used fluid based on historical precedent (particularly in pediatrics).
In pediatrics, a recent propensity-matched analysis of 2,398 patients in the PHIS database found a 2% lower mortality for children receiving LR versus NS. Conversely, in our matched analysis of 4,234 children with septic shock from 382 hospitals in the Premier Healthcare Alliance, we could not demonstrate superiority of LR or NS. However, we noted that highly selective use of LR made it impossible to fully eliminate confounding factors and we concluded that these retrospective data are best used to support equipoise rather than declare NS and LR to be of equal benefit. To definitively test the comparative effectiveness of NS versus balanced fluids, a well-powered randomized controlled trial (RCT) is necessary.
- Cancer Related
- Healthy Volunteers
- UT Southwestern Principal Investigator
- JEANNETTE YOU JIN DODSON
CHILDRENS HOSPITAL OF PHILADELPHIA
[Truncated from IRB]